Recently, temozolomide (TMZ), a myelosuppressive alkylating chemotherapy, has shown a benefit in patients with glioblastoma multiformes (GBM), but median survival is still less than 15 months. Moreover, these conventional chemotherapies lack specificity and result in incapacitating damage to surrounding normal brain and systemic tissues. Immunotherapy may provide an opportunity to eliminate altered neoplastic cells without adding additional toxicity to multi-modality therapy, but the lymphopenia induced by cycles of adjuvant TMZ, now the standard-of-care in patients with GBM, would be predicted to curtail the induction of productive immune responses. However, when given to patients with newly diagnosed glioblastoma multiforme during the recovery from TMZ-induced lymphopenia, the investigators demonstrated that a vaccine targeting a EGFRvIII mutation on GBM induced strong immunologic responses in all vaccinated patients that were accompanied by complete radiographic responses in patients with residual disease and prolonged survival compared to matched historical controls. However, the EGFRvIII mutation is expressed in only about a third of GBMs, limiting the number of patients who may benefit from this therapy and highlighting the need to target more ubiquitously expressed antigens. The recent discovery that greater than 90% of GBMs are associated with tumor-restricted reactivation of human cytomegalovirus (CMV) provides an opportunity to leverage the well characterized viral antigens of CMV as tumor-specific targets. Following a developmental pathway used successfully to advance EGFRvIII specific vaccines to large scale efficacy trials and commercialization, the investigators propose to evaluate the preclinical and clinical advancement of peptide vaccines targeting the immunodominant antigens of CMV. The objectives of this phase I STTR proposal are to finalize the composition of a multi-component peptide vaccine targeting CMV antigens through investigation of the impact of peptide length, hapten conjugation, and the inclusion of class II-restricted helper T cell epitopes on immunologic responses in HLA transgenic mice, and to determine the impact of vaccine dose and timing with respect to administration of TMZ in order to define variables worthy of investigation within the context of early phase clinical trials. PUBLIC HEALTH RELEVANCE: The significance of this research is that it may advance a new therapy for malignant brain tumors as well as provide a strategy for treatment that can be applied to many other cancers. Improved therapy for cancer has significant potential to improve public health and quality of life for patients affected by malignant disease.